Methods of using dihydropteridinones

ABSTRACT

Disclosed are dihydropteridinones of the formula (I):  
                 
 
     wherein the groups X, R 1 , R 2 , R 3 , R 4 , R 5  and R 7  have the meanings given in the claims and specification, the isomers thereof, processes and intermediates for preparing these dihydropteridinones as well as the use thereof as pharmaceutical compositions.

APPLICATION DATA

[0001] This application is a continuation of U.S. application Ser. No.10/226,710 filed Aug. 23, 2002 which claims benefit to DE 101 43 272.0filed Sep. 4, 2001 and U.S. provisional application No. 60/332681 filedNov. 14, 2001.

FIELD OF THE INVENTION

[0002] The present invention relates to new dihydropteridinones ofgeneral formula (I)

[0003] wherein the groups X, R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ have themeanings given in the claims and specification, the isomers thereof,processes for preparing these dihydropteridinones and the use thereof aspharmaceutical compositions.

BACKGROUND TO THE INVENTION

[0004] Pteridinone derivatives are known from the prior art as activesubstances with an antiproliferative activity. WO 01/019825 describesthe use of pteridinone derivatives for the treatment of neoplastic andviral diseases. The resistance of many types of tumours calls for thedevelopment of new pharmaceutical compositions for combating tumours.

[0005] The aim of the present invention is to prepare new compounds withan antiinflammatory and antiproliferative activity.

DETAILED DESCRIPTION OF THE INVENTION

[0006] Surprisingly it has been found that compounds of general formula(I) wherein the groups X and R¹ to R⁷ have the meanings givenhereinafter act as inhibitors of specific cell cycle kinases. Thus, thecompounds according to the invention may be used for example to treatdiseases connected with the activity of specific cell cycle kinases andcharacterised by excessive or abnormal cell proliferation.

[0007] The present invention therefore relates to compounds of generalformula (I)

[0008] wherein

[0009] R¹ denotes a group selected from among hydrogen, NH₂, XH, halogenand a C₁-C₃-alkyl group optionally substituted by one or more halogenatoms,

[0010] R² denotes a group selected from among hydrogen, CHO, XH,—X—C₁-C₂-alkyl and an optionally substituted C₁-C₃-alkyl group,

[0011] R³, R⁴ which may be identical or different denote a groupselected from among optionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,C₂-C₁₀-alkynyl, aryl, heteroaryl, C₃-C₈-cycloalkyl,C₃-C₈-heterocycloalkyl, —X-aryl, —X-heteroaryl, —X-cycloalkyl,—X-heterocycloalkyl, —NR⁸-aryl, —NR⁸-heteroaryl, —NR⁸-cycloalkyl and—NR⁸-heterocycloalkyl, or a group selected from among hydrogen, halogen,COXR⁸, CON(R⁸)₂, COR⁸ and XR⁸, or

[0012] R³ and R⁴ together denote a 2- to 5-membered alkyl bridge whichmay contain 1 to 2 heteroatoms,

[0013] R⁵ denotes hydrogen or a group selected from among optionallysubstituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, aryl,heteroaryl and —C₃-C₆-cycloalkyl, or

[0014] R³ and R⁵ or R⁴ and R⁵ together denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 to 2 heteroatoms,

[0015] R⁶ denotes optionally substituted aryl or heteroaryl,

[0016] R⁷ denotes hydrogen or —CO—X—C₁-C₄-alkyl, and

[0017] X in each case independently of one another denotes O or S,

[0018] R⁸ in each case independently of one another denotes hydrogen ora group selected from among optionally substituted C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl and phenyl,

[0019] optionally in the form of the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.

[0020] Preferred compounds of formula (I) are those wherein

[0021] X and R⁶ have the meaning indicated, and

[0022] R¹ denotes hydrogen,

[0023] R² denotes a group selected from among a CHO, OH, and CH₃ group,

[0024] R³, R⁴ which may be identical or different denote a groupselected from among hydrogen, optionally substituted C₁-C₆-alkyl,C₂-C₆-alkenyl, C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, or

[0025] R³ and R⁴ together denote a C₂-C₅-alkyl bridge,

[0026] R⁵ denotes a group selected from among optionally substitutedC₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl, C₃-C₆-cycloalkyl andC₃-C₆-cycloalkenyl, or

[0027] R³ and R⁵ or R⁴ and R⁵ together denote a saturated or unsaturatedC₃-C₄-alkyl bridge which may contain 1 to 2 heteroatoms, and

[0028] R⁷ denotes hydrogen,

[0029] optionally in the form of the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.

[0030] Particularly preferred compounds of formula (I) are those wherein

[0031] R¹-R⁵, R⁷, R⁸ and X have the meaning indicated, and

[0032] R⁶ denotes a group of general formula

[0033] wherein

[0034] n denotes 1, 2, 3 or 4,

[0035] R⁹ denotes a group selected from among optionally substitutedC₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, —CONH—C₁-C₁₀-alkylene,—O-aryl, —O-heteroaryl, —O-cycloalkyl, —O-heterocycloalkyl, aryl,heteroaryl, cycloalkyl and heterocycloalkyl or a group selected fromamong —O—C₁-C₆-alkyl-Q¹, —CONR⁸—C₁-C₁₀-alkyl-Q¹,—CONR⁸—C₂-C₁₀-alkenyl-Q¹, —CONR⁸—Q², halogen, OH, —SO₂R⁸, —SO₂N(R⁸)₂,—COR⁸,—COOR⁸, —N(R⁸)₂, —NHCOR⁸, CONR⁸OC₁-C₁₀ alkylQ¹ and CONR⁸OQ²,

[0036] Q¹ denotes hydrogen, —NHCOR⁸, or a group selected from among anoptionally substituted —NH-aryl, —NH-heteroaryl, aryl, heteroaryl,C₃-C₈-cycloalkyl- and heterocycloalkyl group,

[0037] Q² denotes hydrogen or a group selected from among an optionallysubstituted aryl, heteroaryl, C₃-C₈-heterocycloalkyl, C₃-C₈-cycloalkyl-and C₁-C₄-alkyl-C₃-C₈-cycloalkyl group,

[0038] R¹⁰ which may be identical or different denotes a group selectedfrom among optionally substituted C₁-C₆-alkyl , C₂-C₆-alkenyl andC₂-C₆-alkynyl, —O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl, —O—C₂-C₆-alkynyl,C₃-C₆-heterocycloalkyl and C₃-C₆-cycloalkyl, or a group selected fromamong hydrogen, —CONH₂, —COOR⁸, —OCON(R⁸)₂, —N(R⁸)₂, —NHCOR⁸,—NHCON(R⁸)₂, —NO₂ and halogen, or

[0039] adjacent groups R⁹ and R¹⁰ together denote a bridge of generalformula

[0040] Y denotes O, S or NR¹¹,

[0041] m denotes 0, 1 or 2

[0042] R¹¹ denotes hydrogen or C₁-C₂-alkyl, and

[0043] R¹² denotes hydrogen or a group selected from among optionallysubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,—C₁-C₃-alkyl-phenyl, —C₁-C₃-alkyl-pyridyl, —C₁-C₃-alkyl-pyrazinyl,—C₁-C₃-alkyl-pyrimidinyl and —C₁-C₃-alkyl-pyridazinyl, p1 R¹³ denotesC₁-C₆-alkyl,

[0044] optionally in the form of the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.

[0045] Particularly preferred are compounds of formula (I) wherein

[0046] R³—R⁶, R⁸ and X have the meaning indicated, and

[0047] R¹ denotes hydrogen,

[0048] R² denotes CH₃, and

[0049] R⁷ denotes hydrogen,

[0050] optionally in the form of the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.

[0051] The invention further relates to compounds of formula (I),wherein X and R¹-R⁷ have the meanings indicated, for use aspharmaceutical compositions.

[0052] Of particular importance according to the invention are compoundsof formula (I), wherein X and R¹-R⁷ have the meaning indicated, for useas pharmaceutical compositions with an antiproliferative activity.

[0053] The invention also relates to the use of a compound of formula(I), wherein X and R¹-R⁷ have the meaning indicated, for preparing apharmaceutical composition for the treatment and/or prevention ofcancer, infections, inflammatory and autoimmune diseases.

[0054] The invention also relates to a method of treating and/orpreventing cancer, infections, inflammatory and autoimmune diseases,characterised in that a patient is given an effective amount of acompound of formula (I), wherein X and R¹-R⁷ have the meaningsindicated.

[0055] The invention also relates to pharmaceutical preparations,containing as active substance one or more compounds of general formula(I), wherein X and R¹-R⁷ have the meanings indicated, or thephysiologically acceptable salts thereof, optionally combined withconventional excipients and/or carriers.

[0056] The invention also relates to a process for preparing a compoundof general formula (I),

[0057] wherein

[0058] R¹-R⁷ and X are as hereinbefore defined, characterised in that acompound of general formula (II)

[0059] wherein

[0060] R¹-R⁵ and X are as hereinbefore defined and L is a leaving group,is reacted with an optionally substituted compound of general formula(III)

[0061] wherein

[0062] R⁶ and R⁷ are as hereinbefore defined.

[0063] The invention also relates to a compound of formula (II),

[0064] wherein

[0065] R¹-R⁵ and X are as hereinbefore defined. Compounds of formula(II) are important intermediate products for preparing the compounds offormula (I) according to the invention.

[0066] The invention also relates to a process for preparing a compoundof general formula (I),

[0067] wherein

[0068] R⁶ denotes a group of general formula,

[0069] R⁹ denotes an optionally substituted group —CONH—C₁-C₁₀-alkyleneor a group selected from among —CONR⁸—C₁-C₁₀-alkyl-Q¹,—CONR⁸—C₂-C₁₀-alkenyl-Q¹, —CONR⁸—Q² and —COOR⁸, and

[0070] R¹-R⁵, R⁷, R¹⁰, n and X are as hereinbefore defined,characterised in that a compound of general formula (IA)

[0071] wherein

[0072] R¹ to R⁵, R⁷ and R¹⁰ are as hereinbefore defined, and

[0073] L denotes a leaving group,

[0074] is reacted with a primary or secondary amine to form thecorresponding amide or is reacted with an alcohol to form thecorresponding ester.

[0075] The term alkyl groups, including alkyl groups which are a part ofother groups, denotes branched and unbranched alkyl groups with 1 to 10carbon atoms, preferably 1-6, most preferably 1-4 carbon atoms, such as,for example: methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl,nonyl and decyl. Unless otherwise stated, the abovementioned termspropyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl and decyl include allthe possible isomeric forms. For example, the term propyl includes thetwo isomeric groups n-propyl and iso-propyl, the term butyl includesn-butyl, iso-butyl, sec. butyl and tert.-butyl, the term pentyl includesiso-pentyl, neopentyl, etc.

[0076] In the abovementioned alkyl groups one or more hydrogen atoms mayoptionally be replaced by other groups. For example these alkyl groupsmay be substituted by the halogen atoms fluorine, chlorine, bromine oriodine. The substituents fluorine and chlorine are preferred. Thesubstituent chlorine is particularly preferred. All the hydrogen atomsof the alkyl group may optionally also be replaced.

[0077] Similarly, in the abovementioned alkyl groups, unless otherwisestated, one or more hydrogen atoms may optionally be replaced forexample by an optionally substituted group selected from among CN,OCOCH₃, aryl, preferably phenyl, heteroaryl, preferably thienyl,thiazolyl, imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated orunsaturated heterocycloalkyl, preferably pyrazolyl, pyrrolidinyl,piperidinyl, piperazinyl or tetrahydro-oxazinyl, an amine group,preferably methylamine, benzylamine, phenylamine or heteroarylamine,saturated or unsaturated bicyclic ring systems, preferablybenzimidazolyl and cycloalkyl, preferably cyclohexyl or cyclopropyl.

[0078] The term alkyl bridge, unless otherwise stated, denotes branchedand unbranched alkyl groups with 2 to 5 carbon atoms, for examplepropylene, isopropylene, n-butylene, iso-butyl, sec. butyl andtert.-butyl etc. bridges. Propylene and butylene bridges areparticularly preferred. In the alkyl bridges mentioned 1 to 2 C-atomsmay optionally be replaced by one or more heteroatoms selected fromamong oxygen, nitrogen or sulphur.

[0079] The term alkenyl groups (including those which are a part ofother groups) denotes branched and unbranched alkylene groups with 2 to10 carbon atoms, preferably 2-6 carbon atoms, most preferably 2-3 carbonatoms, provided that they have at least one double bond. Examplesinclude: ethenyl, propenyl, butenyl, pentenyl etc. Unless otherwisestated, the abovementioned terms propenyl, butenyl, etc also include allthe possible isomeric forms. For example, the term butylene includesn-butenyl, 1-methylpropenyl, 2-methylpropenyl, 1.1-dimethylethenyl,1.2-dimethylethenyl etc.

[0080] In the abovementioned alkenyl groups, unless otherwise stated,one or more hydrogen atoms may optionally be replaced by other groups.For example, these alkyl groups may be substituted by the halogen atomsfluorine, chlorine, bromine or iodine. The substituents fluorine andchlorine are preferred. The substituent chlorine is particularlypreferred. All the hydrogen atoms of the alkenyl group may optionallyalso be replaced.

[0081] The term alkynyl groups (including those which are a part ofother groups) denotes branched and unbranched alkynyl groups with 2 to10 carbon atoms, provided that they have at least one triple bond, forexample ethynyl, propargyl, butynyl, pentynyl, hexynyl etc., preferablyethynyl or propynyl.

[0082] In the abovementioned alkynyl groups, unless otherwise stated,one or more hydrogen atoms may optionally be replaced by other groups.For example, these alkyl groups may be substituted by the halogen atomsfluorine, chlorine, bromine or iodine. The substituents fluorine andchlorine are preferred. The substituent chlorine is particularlypreferred. All the hydrogen atoms of the alkynyl group may optionallyalso be replaced.

[0083] The term aryl denotes an aromatic ring system with 6 to 14 carbonatoms, preferably 6 or 10 carbon atoms, preferably phenyl, which, unlessotherwise stated, may carry one or more of the following substituents,for example: OH, NO₂, CN, —OCHF₂, —OCF₃, —NH₂, halogen, for examplefluorine, chlorine, bromine or iodine, preferably fluorine or chlorine,C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl, mostpreferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably —O-methyl or—O-ethyl, —N-methyl-tetrahydro-oxazinyl, —COOH, —COO—C₁-C₄-alkyl,preferably —COOCH₂CH₃, —COO—C(CH₃)₃ or —COOCH₃, —CONH₂,—CONH—C₁-C₁₀-alkyl, while this alkyl may optionally be furthersubstituted, optionally substituted —CONH—C₃-C₆-cycloalkyl, preferablyoptionally substituted —CONH-cyclopentyl, optionally substituted—CONH-heterocycloalkyl, preferably piperidinyl, pyrrolidinyl orpiperazinyl, optionally substituted —CONH-heteroaryl, preferablyoptionally substituted —CONH-pyridyl, optionally substituted —CONH-aryl,preferably optionally substituted —CONH-phenyl, —CONMeC₁-C₃-alkyl, whilethis alkyl may optionally be further substituted, preferably—CONMeCH₂-pyridyl, benzimidazole or a group of formula

[0084] Examples of 5-10-membered mono- or bicyclic heteroaryl ringswherein up to three C-atoms may be replaced by one or more heteroatomsselected from among oxygen, nitrogen or sulphur include furan,thiophene, pyrrole, pyrazole, imidazole, triazole, tetrazole, pyridine,pyridazine, pyrimidine, pyrazine, triazine, oxazole, isoxazole,thiazole, thiadiazole and oxadiazole, while each of the abovementionedheterocycles may optionally also be annellated onto a benzene ring,preferably benzimidazole, and unless otherwise stated these heterocyclesmay for example carry one or more of the following substituents: OH,NO₂, CN, —OCHF₂, —OCF₃, —NH₂, halogen, preferably fluorine or chlorine,C₁-C₁₀-alkyl, preferably C₁-C₅-alkyl, preferably C₁-C₃-alkyl, mostpreferably methyl or ethyl, —O—C₁-C₃-alkyl, preferably —O-methyl or—O-ethyl, -methyl-N-tetrahydro-oxazinyl, —COOH, —COO—C₁-C₄-alkyl,preferably —COO—C(CH₃)₃ or —COOCH₃, —CONH₂, optionally substitutedphenyl, optionally substituted heteroaryl, preferably optionallysubstituted pyridyl or pyrazinyl, —CONH—C₁-C₁₀-alkyl, while this alkylmay itself optionally be substituted, optionally substituted—CONH—C₃-C₆-cycloalkyl, preferably optionally substituted—CONH-cyclopentyl, optionally substituted —CONH-heteroaryl, preferablyoptionally substituted —CONH-pyridyl, optionally substituted —CONH-aryl,preferably optionally substituted —CONH-phenyl, —CONMeC₁-C₃-alkyl, whilethis alkyl may itself optionally be substituted, preferably—CONMeCH₂-pyridyl, benzimidazole or a group of formula

[0085] The term cycloalkyl groups denotes, for example, saturated orunsaturated cycloalkyl groups with 3-8 carbon atoms, for examplecyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl,cyclohexenyl, cycloheptyl or cyclooctyl, preferably cyclopropyl,cyclopentyl or cyclohexyl, while each of the abovementioned cycloalkylgroups may optionally also carry one or more substituents, preferably═O, or may be annellated to a benzene ring.

[0086] “═O” denotes an oxygen atom linked via a double bond.

[0087] The term heterocycloalkyl groups, unless otherwise described inthe definitions, may denote 5-, 6- or 7-membered, saturated orunsaturated heterocycles, which may contain nitrogen, oxygen or sulphuras heteroatoms, for example tetrahydrofuran, tetrahydrofuranon,γ-butyrolactone, α-pyran, γ-pyran, dioxolane, tetrahydropyran, dioxane,dihydrothiophene, thiolan, dithiolan, pyrroline, pyrrolidine,pyrazoline, pyrazolidine, imidazoline, imidazolidine, tetrazole,piperidine, pyridazine, pyrimidine, pyrazine, piperazine, triazine,tetrazine, morpholine, thiomorpholine, diazepan, oxazine,tetrahydro-oxazinyl, isothiazole and pyrazolidine, preferably pyrazolyl,pyrrolidinyl, piperidinyl, piperazinyl or tetrahydro-oxazinyl, while theheterocycle may optionally be substituted.

[0088] Generally, the term halogen denotes fluorine, chlorine, bromineor iodine.

[0089] The leaving group L denotes either identical or different leavinggroups such as for example chlorine, bromine, iodine, methanesulphonyl,trifluoromethanesulphonyl or p-toluenesulphonyl, preferably chlorine.

[0090] The compounds according to the invention may be present in theform of the individual optical isomers, mixtures of the individualenantiomers, diastereomers or racemates, in the form of the tautomersand also in the form of the free bases or the corresponding acidaddition salts with pharmacologically acceptable acids—such as forexample acid addition salts with hydrohalic acids, for examplehydrochloric or hydrobromic acid, or organic acids, such as for exampleoxalic, fumaric, diglycolic or methanesulphonic acid.

[0091] The substituent R¹ may denote a group selected from amonghydrogen, NH₂, XH, preferably OH, halogen, preferably fluorine orchlorine and a C₁-C₃-alkyl group optionally substituted by one or more,preferably one, two or three halogen atoms, preferably fluorine orchlorine, preferably methyl or ethyl. Most preferably, the substituentR¹ is hydrogen .

[0092] The substituent R² may denote a group selected from amonghydrogen, CHO, XH, preferably OH, —X—C₁-C₂-alkyl, preferably —O—CH₃ or—O—CH₂CH₃, and an optionally substituted C₁-C₃-alkyl group, while thealkyl group preferably consists of 1 to 2 carbon atoms, particularlypreferably a carbon atom and may optionally be substituted, preferablyby halogen atoms, most preferably by fluorine atoms. In particular, thesubstituent R² denotes methyl.

[0093] The substituents R³ and R⁴ may be identical or different and mayrepresent a group selected from among optionally substitutedC₁-C₁₀-alkyl, preferably C₁-C₆-alkyl, preferably C₁-C₄-alkyl, mostpreferably methyl, ethyl or propyl, particularly preferably methyl orethyl, C₂-C₁₀-alkenyl, preferably ethenyl or propenyl, preferablyethenyl, C₂-C₁₀-alkynyl, preferably ethynyl or propynyl, aryl,preferably optionally substituted phenyl, heteroaryl, C₃-C₈-cycloalkyl,preferably cyclopropyl and cyclobutyl, C₃-C₈-heterocycloalkyl, —X-aryl,—X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR⁸-aryl,—NR⁸-heteroaryl, —NR⁸-cycloalkyl and —NR⁸-heterocycloalkyl, or

[0094] a group selected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂,COR⁸ and XR⁸, preferably hydrogen, or

[0095] the groups R³ and R⁴ may together denote a 2- to 5-membered alkylbridge, preferably an ethylene, propylene or butylene bridge , while thepropylene or butylene bridge may contain 1 to 2 heteroatoms, preferablyoxygen, nitrogen or sulphur, most preferably an ethylene bridge.

[0096] Most preferably, the substituent R³ denotes methyl or ethyl. Thesubstituent R⁴ most preferably denotes hydrogen or methyl. Particularlypreferred are compounds wherein R³ and R⁴ represent methyl.

[0097] All the groups mentioned in the definition of R³ and R⁴ mayoptionally be substituted.

[0098] The group R⁵ may contain hydrogen or a group selected from amongoptionally substituted C₁-C₁₀-alkyl, for example C₁-C₆-alkyl-aryl orC₁-C₆-alkyl-heteroaryl, preferably C₁-C₆-alkyl, most preferablyC₁-C₅-alkyl, particularly preferably propyl, butyl, pentyl, hexyl,—CH₂-cyclohexyl, (CH₂)₁₋₂cyclopropyl or (CH₂)₄—OCOCH₃, C₂-C₁₀-alkenyl,preferably propenyl, butenyl, pentenyl or hexenyl, preferably propenylor hexenyl, C₂-C₁₀-alkynyl, preferably propynyl, butynyl or pentynyl,preferably propynyl, aryl, preferably phenyl, heteroaryl,—C₃-C₆-cycloalkyl, preferably cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl and -C₃-C₆-cycloalkenyl, preferably cyclohexenyl orcyclopentenyl, or the substituents R³ and R⁵ or R⁴ and R⁵ togetherdenote a saturated or unsaturated C₃-C₄-alkyl bridge which may contain 1to 2 heteroatoms, preferably oxygen, sulphur or nitrogen.

[0099] All the groups mentioned in the definition of R⁵ may optionallybe substituted.

[0100] The substituent R⁶ may denote optionally substituted aryl, orheteroaryl, preferably aryl, preferably phenyl.

[0101] Most preferably, the substituent R⁶ denotes a phenyl group, whichmay be substituted by one of the groups R⁹ and R¹⁰ describedhereinafter, while the phenyl ring may carry one of the groups R⁹,preferably in the para position, and one, two, three or four, preferablyone or two, of the groups R¹⁰, preferably in the ortho or meta position.

[0102] The substituent R⁷ may denote hydrogen or —CO—X—C₁-C₄-alkyl,preferably hydrogen.

[0103] X denotes, in each case independently of one another, O or S,preferably O.

[0104] The groups R⁸ mentioned in the definitions of the substituents R³and R⁴ represent, independently of one another in each case, hydrogen ora group selected from among optionally substituted C₁-C₄-alkyl,C₂-C₄-alkenyl, C₂-C₄-alkynyl and phenyl, preferably hydrogen orC₁-C₂-alkyl.

[0105] The substituent R⁹ may represent a group selected from amongoptionally substituted C₁-C₆-alkyl, preferably C₁-C₄-alkyl, preferablymethyl, ethyl or propyl, most preferably methyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, —CONH—C₁-C₁₀-alkylene, preferably —CONH—C₁-C₃-alkylene,preferably —CONH—C₁-C₂-alkylene, —O-aryl, preferably O—C₆-C₁₀-aryl, mostpreferably O-phenyl, —O-heteroaryl, —O-cycloalkyl, preferablyO—C₃-C₆-cycloalkyl, most preferably O-cyclopropyl, —O-heterocycloalkyl,aryl, preferably C₆-C₁₀-aryl, most preferably phenyl, heteroaryl,cycloalkyl, preferably C₃-C₆-cycloalkyl, most preferably cyclopropyl,and heterocycloalkyl, or a group selected from among —O—C₁-C₆-alkyl-Q¹,—CONR⁸—C₁-C₁₀-alkyl-Q¹, —CONR⁸—C₁-C₁₀-alkenyl-Q¹, —CONR⁸Q², halogen, forexample fluorine, chlorine, bromine or iodine, OH, —SO₂R⁸, —SO₂N(R⁸)₂,—COR⁸,—COOR⁸, —N(R⁸)₂, —NHCOR⁸, CONR⁸OC₁-C₁₀-alkylQ¹ and CONR⁸OQ², whereQ¹ and Q² are as hereinbefore defined.

[0106] Preferably, R⁹ denotes one of the following groups—CONH—C₁-C₁₀-alkyl, preferably —CONH—C₁-C₃-alkyl, most preferably—CONH—C₁-C₂-alkyl, while this alkyl may itself optionally besubstituted, by CN, optionally substituted aryl, preferably optionallysubstituted phenyl, heteroaryl, preferably thienyl, thiazolyl,imidazolyl, pyridyl, pyrimidyl or pyrazinyl, saturated or unsaturatedheterocycloalkyl, preferably pyrazolyl, pyrrolidinyl, piperidinyl,piperazinyl or tetrahydro-oxazinyl, an amine group, preferablymethylamine, benzylamine, phenylamine or heteroarylamine, saturated orunsaturated bicyclic ring systems, preferably benzimidazolyl andcycloalkyl, preferably cyclohexyl. Moreover R⁹ preferably denotes—CONH-heteroaryl, preferably —CONH-pyridyl, —CONH—C₃-C₁₀-cycloalkyl,preferably —CONH-cyclopropyl —CONH-cyclobutyl or —CONH-cyclopentyl, mostpreferably —CONH-cyclopropyl; —CONH—C₃-C₁₀-heterocycloalkyl,—CONH—C₆-C₁₀-aryl, preferably —CONH-phenyl, COO—C₁-C₃-alkyl, mostpreferably COOCH₃, COOH, halogen, preferably F or chlorine, OH or agroup of formula

[0107] All the groups mentioned in the definition of R⁹ may optionallybe substituted, preferably by one or more of the groups selected fromamong OH, OCH₃, Cl, F, CH₃, COOH, CONHCH₂Ph and CONHCH₂-pyrazinyl-CH₃.

[0108] The substituent R¹⁰ may be identical or different in each caseand may denote a group selected from among optionally substitutedC₁-C₆-alkyl , preferably C₁-C₃-alkyl, C₂-C₆-alkenyl, preferablyC₂-C₃-alkenyl and C₂-C₆-alkynyl, preferably C₂-C₃-alkynyl,—O—C₁-C₆-alkyl, preferably —O—C₁-C₃-alkyl, —O—C₂-C₆-alkenyl,—O—C₂-C₆-alkynyl, C₃-C₆-heterocycloalkyl and C₃-C₆-cycloalkyl, or agroup selected from among hydrogen, —CONH₂, —COOR⁸, —OCON(R⁸)₂, —N(R⁸)₂,—NHCOR⁸, —NHCON(R⁸)₂, —NO₂ and halogen, for example fluorine, chlorine,bromine or iodine.

[0109] Preferably, the substituent R¹⁰ denotes hydrogen, methyl,methoxy, fluorine or chlorine, most preferably hydrogen or methoxy,particularly preferably methoxy.

[0110] Adjacent groups R⁹ and R¹⁰ may together denote a bridge ofgeneral formula

[0111] wherein

[0112] Y denotes O, S or NR¹¹, preferably NR¹¹,

[0113] m denotes 0, 1 or 2, preferably 1,

[0114] R¹¹ denotes hydrogen or C₁-C₂-alkyl, preferably hydrogen ormethyl, most preferably hydrogen,

[0115] R¹² denotes hydrogen or a group selected from among optionallysubstituted phenyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl,—C₁-C₃-alkyl-phenyl, —C₁-C₃-alkyl-pyridyl, —C₁-C₃-alkyl-pyrazinyl,—C₁-C₃-alkyl-pyrimidinyl and -C₁-C₃-alkyl-pyridazinyl, preferablyphenyl, pyridyl and pyrazinyl, and

[0116] R¹³ denotes C₁-C₆-alkyl, preferably methyl or ethyl.

[0117] The compounds according to the invention may be prepared bysynthesis methods A and B described hereinafter, while the substituentsof general formulae (A1) to (A6) have the meanings given hereinbefore.These methods are to be understood as illustrations of the inventionwithout restricting it to their subject matter.

[0118] Method A

[0119] Step 1A

[0120] A compound of formula (A1) is reacted with a compound of formula(A2) to obtain a compound of formula (A3) (Diagram 1A). This reactionmay be carried out according to WO 0043369 or WO 0043372. Compound (A1)is commercially obtainable, for example, from City Chemical LLC, 139Allings Crossing Road, West Haven, Conn., 06516, USA. Compound (A2) maybe prepared by procedures known from the literature: (a) F. Effenberger,U. Burkhart, J. Willfahrt Liebigs Ann. Chem. 1986, 314-333; b) T.Fukuyama, C.-K. Jow, M. Cheung, Tetrahedron Lett. 1995, 36, 6373-6374;c) R. K. Olsen, J. Org. Chem. 1970, 35, 1912-1915; d) F. E. Dutton, B.H. Byung Tetrahedron Lett. 1998, 30, 5313-5316; e) J. M. Ranajuhi, M. M.Joullie Synth. Commun. 1996, 26, 1379-1384.).

[0121] In Step 1A, 1 equivalent of the compound (A1) and 1 to 1.5equivalents, preferably 1.1 equivalents of a base, preferably potassiumcarbonate, potassium hydrogen carbonate, sodium carbonate or sodiumhydrogen carbonate, calcium carbonate, most preferably potassiumcarbonate, are stirred in a diluent, for example acetone, aqueousacetone, tetrahydrofuran, diethylether or dioxane, preferably acetone ordiethylether, most preferably acetone.

[0122] At a temperature of 0 to 15° C., preferably 5 to 10° C., 1equivalent of an amino acid of formula (A2), dissolved in an organicsolvent, for example acetone, tetrahydrofuran, diethylether or dioxane,preferably acetone, is added dropwise.

[0123] The reaction mixture is heated to a temperature of 18° C. to 30°C., preferably about 22° C., with stirring and then stirred for afurther 10 to 24 hours, preferably about 12 hours. Then the diluent isdistilled off, the residue is combined with water and the mixture isextracted two to three times with an organic solvent, such asdiethylether or ethyl acetate, preferably ethyl acetate. The combinedorganic extracts are dried and the solvent is distilled off. The residue(compound A3) may be used in Step 2 without any prior purification.

[0124] Step 2A

[0125] The compound obtained in Step 1A (A3) is reduced at the nitrogroup and cyclised to form the compound of formula (A4) (Diagram 2A).

[0126] In Step 2A, 1 equivalent of the nitro compound (A3) is dissolvedin an acid, preferably glacial acetic acid, formic acid or hydrochloricacid, preferably glacial acetic acid, and heated to 50 to 70° C.,preferably about 60° C. Then a reducing agent, for example zinc, tin oriron, preferably iron filings, is added to complete the exothermicreaction and the mixture is stirred for 0.2 to 2 hours, preferably 0.5hours, at 100 to 125° C., preferably at about 117° C. After cooling toambient temperature the iron salt is filtered off and the solvent isdistilled off. The residue is taken up in a solvent or mixture ofsolvents, for example ethyl acetate or dichloromethane/methanol 9/1 andsemisaturated NaCl solution, and filtered through kieselgur, forexample. The organic phase is dried and evaporated down. The residue(compound (A4)) may be purified by chromatography or by crystallisationor used as the crude product in Step 3A of the synthesis.

[0127] Step 3A

[0128] The compound obtained in Step 2A (A4) may be reacted byelectrophilic substitution as shown in Diagram 3A to obtain the compoundof formula (A5).

[0129] In Step 3A 1 equivalent of the amide of formula (A4) is dissolvedin an organic solvent, for example dimethylformamide ordimethylacetamide, preferably dimethylacetamide, and cooled to about −5to 5° C., preferably 0° C. Then 0.9 to 1.3 equivalents of sodium hydrideand 0.9 to 1.3 equivalents of alkyl halide, for example methyl iodide,are added. The reaction mixture is stirred for 0.1-3 hours, preferablyabout 1 hour, at about 0 to 10° C., preferably at about 5° C., and mayoptionally be left to stand for a further 12 hours at this temperature.The reaction mixture is evaporated down and extracted with water and anorganic solvent, preferably dichloromethane or ethyl acetate. Theorganic phases are evaporated down. The residue (compound (A5)) may bepurified by chromatography, preferably over silica gel.

[0130] Step 4A

[0131] The amination of the compound (A5) obtained in Step 3A to yieldthe compound of formula (A7) (Diagram 4A) may be carried out using themethods known from the literature of variants 4.1 A (a) M. P. V.Boarland, J. F. W. McOmie J. Chem. Soc. 1951, 1218-1221; b) F. H. S.Curd, F. C. Rose J. Chem. Soc. 1946, 343-348., 4.2 A (a) Banks J. Am.Chem. Soc. 1944, 66,1131 b) Ghosh and Dolly J. Indian Chem. Soc. 1981,58, 512-513.

[0132] For example, in variant 4.1 A, 1 equivalent of the compound (A5)and 1 to 3 equivalents, preferably about 2 equivalents of the compound(A6) are heated without a solvent or in an organic solvent such as forexample sulpholane, dimethylformamide, dimethylacetamide, toluene,N-methylpyrrolidone, dimethylsulphoxide or dioxane, preferablysulpholane, for 0.1 to 4 hours, preferably 1 hour, at 100 to 220° C.,preferably at about 160° C. After cooling, the product (A7) iscrystallised by the addition of organic solvents or mixtures ofsolvents, e.g. diethylether/methanol, ethyl acetate, methylene chloride,or diethylether, preferably diethylether/methanol 9/1, or purified bychromatography.

[0133] For example, in variant 4.2 A, 1 equivalent of the compound (A5)and 1 to 3 equivalents of the compound (A6) are stirred with acid, forexample 1-10 equivalents of 10-38% hydrochloric acid and/or an alcohol,for example ethanol, propanol, butanol, preferably ethanol, at refluxtemperature for 1 to 48 hours, preferably about 5 hours.

[0134] The product precipitated (A7) is filtered off and optionallywashed with water, dried and crystallised from a suitable organicsolvent.

[0135] If R⁶ denotes an optionally substituted benzimidazole, thepreparation of the compounds (A6) using methods known from theliterature may be carried out as shown in the following diagram, forexample:

[0136] Accordingly, for example, 33 mmol of the compound (Z1), 49 mmolof the compound (Z2) and 49 mmol of1-ethoxycarbonyl-2-ethoxydihydroquinoline (EEDQ) are stirred into 50 mlof an organic solvent, preferably dimethylformamide, at about 100 to130° C., preferably at about 115° C., 1 to 4 hours, preferably about 3hours. Then the cooled reaction solution is added to 50 to 400 ml,preferably about 200 ml of a water/ethyl acetate mixture (mixing ratioabout 1:1). The crystals formed (Z3) are suction filtered and washed.

[0137] Then 4.2 mmol of the compound (Z3) are stirred with 12.5 mmol oftin(II)chloride and 30 mmol of potassium carbonate in about 50 ml of anorganic diluent, preferably ethyl acetate, at about 22° C. for 4 to 48hours, preferably about 24 hours. After the addition of 22 g ofkieselgur the mixture is extracted with an organic diluent or mixture ofdiluents, preferably with a mixture of dichloromethane/methanol (9:1),the combined extracts are evaporated down and the precipitate formed(Z4) or the crystals produced (Z4) is or are isolated.

[0138] Step 5A

[0139] If R⁹ denotes —CONR⁸—C₁-C₁₀-alkyl-Q¹, —CONH—C₁-C₅-alkylene or—CONR⁸—Q², wherein the substituents have the meanings givenhereinbefore, the compounds according to the invention may be preparedusing methods known from the literature, for example as shown in Diagram5A.

[0140] The compound (A7′) obtained in Step 4A may be reacted either bysaponification and subsequent amination to obtain the amide of generalformula (A10) (Diagram (5A) variant 5.1 A), or by saponification, withsubsequent conversion into the acid chloride (A9) and subsequentamination (Diagram (5A) variant 5.2A).

[0141] Variant 5.1 A:

[0142] In variant 5.1 A, for example, 20 mmol of the ester (A7′) areheated in about 100 ml of a base, preferably 1N sodium hydroxidesolution or lithium hydroxide solution and about 500 ml of an alcohol,for example with ethanol, dioxane or methanol, preferably methanol,until the ester is completely reacted. Then the alcohol is distilledoff. The residue is taken up in about 200 ml of water and acidifiedwhile cooling with acid, for example hydrochloric acid, preferably with2 N hydrochloric acid. The product (A8) is filtered off and dried.

[0143] For example, about 0.5 mmol of the compound (A8) are dissolvedwith about 0.5 mmol of O-benzotriazolyl-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TBTU) and about 1.4 mmol of diisopropylethylamine(DIPEA) in about 5 ml of an organic diluent, for exampletetrahydrofuran, dimethylformamide, N-methylpyrrolidone,dimethylacetamide, preferably dimethylformamide. After the addition ofabout 0.75 mmol of an amine which forms the substituent R⁹, the reactionmixture is stirred for 0.1 to 24 hours, preferably about 12 hours at 20°C. to 100° C. The product of formula (A10) is obtained for example bycrystallisation or chromatographic purification.

[0144] Variant 5.2 A:

[0145] In variant 5.2 A about 1 mmol of the acid (A8) for example issuspended in about 2.7 ml of thionyl chloride. The mixture is heated to40° C. to 80° C., preferably about 50° C., and at constant temperature 2to 10 drops, preferably about 3 drops of dimethylformamide are added tothe reaction mixture with stirring. Then stirring is continued at 90° C.until the reaction is complete. Excess thionyl chloride is distilledoff. About 1 mmol of the acid chloride formed (A9) are dissolved inabout 30 ml of an organic diluent, for example dichloromethane. Afterthe addition of an amine which forms the substituent R⁹ the mixture isstirred at about 22° C. The precipitate formed is filtered off andwashed with water. The residue remaining is washed with an organicdiluent, for example methanol. The mother liquor is purified, forexample by chromatography, and evaporated down. The product (A10)remains.

[0146] Method B

[0147] Alternatively to the methods described above, after Step 1A firstthe compound (A3) may be aminated and then the product (B1) may becyclised to yield the compound (B2), as shown in Diagram B. Furthersubstitution of the compound (B2) to yield the compound (A7) may becarried out for example as in Step 3A.

[0148] The new compounds of general formula (I) may be synthesisedanalogously to the following examples of synthesis. These Examples are,however, intended only as examples of procedures to illustrate theinvention further, without restricting the invention to their subjectmatter.

EXAMPLE 63 AND EXAMPLE 109

[0149] In order to synthesise the compounds 63 and 109, first anintermediate compound 4

[0150] is prepared as described hereinafter.

[0151] 38.9 ml (0.263 mol) of ethyl 2-bromobutyrate and 36.4 g (0.263mol) of potassium carbonate were placed in 350 ml of ethyl acetate, andthen 46.7 ml (0.402 mol) of isoamylamine, dissolved in 70 ml of ethylacetate, were rapidly added dropwise. The mixture was refluxed for 20 h.The salt formed was filtered off, the filtrate was concentrated byevaporation, combined with 50 ml of toluene and again evaporated todryness.

[0152] Yield: 54.3 g of a compound 1 (red oil)

[0153] 54.3 g of compound 1, dissolved in 400 ml acetone, and 30.7 g(0.222 mol) of potassium carbonate were cooled to 8° C. with stirring,combined with a solution of 43.1 g (0.222 mol) of2,4-dichloro-5-nitropyrimidine in 250 ml acetone and then stirred for 24h at RT.

[0154] The suspension formed was concentrated by evaporation, theresidue was extracted with water and ethyl acetate, the organic phasewas washed with water and NaCl solution, dried over MgSO₄ and evaporatedto dryness.

[0155] Yield: 87.3 g of a compound 2 (brown oil)

[0156] 44.1 g of compound 2 were dissolved in 800 ml glacial acetic acidand heated to 65° C. and 36 g of iron filings were added batchwise. Thenthe mixture was stirred for 3 h at 70° C., the precipitate was filteredoff and the filtrate was concentrated by evaporation.

[0157] The residue was applied to silica gel in dichloromethane/methanol90:10, concentrated by evaporation and purified by column chromatography(eluant: ethyl acetate/cyclohexane 1:1).

[0158] The residue was precipitated from ethyl acetate/petroleum ether.

[0159] Yield: 16.1 g of a compound 3 (beige powder)

[0160] 16.1 g of compound 3 were dissolved in 75 ml of dimethylacetamideand cooled to 5° C. under a nitrogen atmosphere with stirring. Then 2.51g (0.063 mol) of NaH, 60% dispersion in mineral oil, was added,whereupon the temperature temporarily rose to 16° C. After 30 minutes3.94 ml (0.063 mol) of methyl iodide, dissolved in 75 mldimethylacetamide, were added, and the mixture was stirred for 24 h at22° C.

[0161] The solvent was concentrated by evaporation, combined with 200 mlof water and the precipitate formed was suction filtered, then extractedby stirring with petroleum ether.

[0162] Yield: 15.1 g of a compound 4 (yellow powder)

[0163]¹H-NMR (250 MHz):=7.80 (1H, s), 4.35 (m, 1H), 3.92 (m, 1H), 3.22(s, 3H), 3.14 (m, 1H), 1.81 (m, 2H), 1.60-1.40 (m, 3H), 0.90 (m, 6H),0.70 (t, 3H).

SYNTHESIS OF EXAMPLE 63

[0164] 2.5 g of compound 4, 1.43 g of 4-amino-3-methoxybenzoic acid,1.25 mL of conc. hydrochloric acid, 150 mL of dist. water and 37.5 mL ofethanol were refluxed for 10 h. The precipitate was filtered off, washedwith water and extracted by stirring in methanol. Then the precipitatewas recrystallised using petroleum ether and ether.

[0165] Yield: 1.6 g of a compound 5 (white powder)

[0166] 0.2 g of compound 5, 5 mL of benzylamine, 0.16 g of TBTU, 0.17 gof DIPEA were dissolved in 2 ml of dimethylformamide (DMF) and stirredfor 48 h at ambient temperature. Then the reaction mixture was taken upin methylene chloride, washed with water and the organic phase wasevaporated down. When petroleum ether/ethyl acetate 9:1 was added theproduct was precipitated in the form of light beige crystals.

[0167] Yield: 0.18 g. Melting point: 178° C.

SYNTHESIS OF EXAMPLE 109

[0168] 5 g of 2 amino-5-nitroaniline, 6.03 g of 4-pyridylcarboxylicacid, 12.1 g of EEDQ are dissolved in 50 mL of DMF and stirred at 115°C. for 1.75 h, then the DMF is distilled off in vacuo and the reactionmixture is then heated to 180° C. for 1 h. The residue is taken up in 30mL of DMF and combined with 200 mL of water and 100 mL of ethyl acetate.The crystal slurry obtained is filtered off and washed with water, ethylacetate and ether.

[0169] Yield: 5.8 g of a compound 6

[0170] 2 g of the compound 6 is combined with 0.2 g of 5% Pd/C in 30 mLof ethanol and hydrogenated in the presence of hydrogen. It is thenevaporated down and crystallised from ethanol and toluene.

[0171] Yield: 1.75 g of white powder of a compound 7.

[0172] 0.2 g of the compound 5, 0.28 g of the compound 7, 0.001 g ofsodium-tert. butoxide, 2.5 mL of ethyleneglycol dimethylether, 0.006 gof palladium(II) acetate and 0.22 g of2-(di-tert.-butylphospino)biphenyl are dissolved in 1.5 mL ofN-methylpyrrolidone (NMP). Then the mixture is heated to 160° C. for 0.5h. The reaction mixture is then purified over 20 g of silica gel and theproduct is crystallised from ether, ethyl acetate and petroleum ether.

[0173] Yield: 0.04 g of yellow crystals. Melting point: 180° C.

EXAMPLE 218, 58 AND 4

[0174] In order to synthesise the compounds 218, 58 and 4, first anintermediate compound 11

[0175] is prepared as described hereinafter.

[0176] 55.8 g of DL-alanine methyl ester×HCl were dissolved in 500 ml ofmethanol, then 76.1 ml of 30% sodium methoxide solution was added andthe salt was filtered off. 37.8 g of trimethylacetaldehyde were added tothe filtrate, then it was left to stand for 22 h. Then 9.5 g of 10% Pd/Cwas added and the mixture was hydrogenated for 3.1 h at 0.5 bar and 20°C. The reaction mixture was suction filtered through kieselgur andconcentrated by evaporation. The residue was taken up in diethylether,the salts were filtered through kieselgur and the filtrate wasconcentrated by evaporation.

[0177] Yield: 55.8 g of a compound 8 (clear liquid)

[0178] 48.5 g of 2,4-dichloro-5-nitropyrimidine were placed in 400 ml ofdiethylether, 41.0 g of potassium hydrogen carbonate in 400 ml of waterwere added, and the mixture was cooled to −5° C. 43.3 g of compound 8were dissolved in 400 ml of diethylether and added dropwise at −5° C.The mixture was stirred for 1 h at −5° C. and for 2 h at 0° C., thenheated to ambient temperature and the reaction mixture was left to standfor 24 h.

[0179] The organic phase was separated off, dried over MgSO₄ andevaporated to dryness.

[0180] Yield: 79.2 g of a compound 9 (yellow resin)

[0181] 79.0 g of compound 9 were dissolved in 1000 ml of glacial aceticacid and heated to 70° C. After the removal of the heat source 52 g ofiron was added batchwise. The temperature rose to about 110° C. and themixture was stirred for 1 h at this temperature. The suspension wasfiltered while hot and the filtrate was concentrated by evaporation.

[0182] The residue was taken up in ethyl acetate and combined with 150ml of conc. HCl, the organic phase was separated off and the aqueousphase extracted several times with dichloromethane. The combined organicphases were concentrated by evaporation, applied to silica gel andpurified by column chromatography (eluant: petroleum ether/ethyl acetate1:1).

[0183] As the isolated substance was still highly contaminated, it wasagain purified over silica gel. The desired compound crystallised out,the crystals were suction filtered. The mother liquor was concentratedby evaporation and recrystallised from ethyl acetate/diethylether.

[0184] Yield: 17.63 g of a compound 10

[0185] 7.6 g of the compound 10 and 6.4 ml of methyl iodide were placedin 75 ml of dimethylacetamide (DMA) and cooled to −15° C. 1.25 g of NaH,60% dispersion in mineral oil, was added batchwise, and stirred for 30min. at −10° to −5° C. Then 150 ml of ice water were added, the crystalswere suction filtered and washed with water and petroleum ether. Thecrystals were taken up in dichloromethane, filtered through kieselgurand the filtrate was evaporated to dryness. It was recrystallised frompetroleum ether.

[0186] Yield: 6.3 g of compound 11 (beige crystals) ¹H-NMR (250MHz):=7.73 (1H, s), 4.35 (d, 1H), 4.25 (m, 1H), 3.35 (s, 3H), 2.55 (d,1H), 1.31 (d, 3H), 0.95 (s, 9H).

SYNTHESIS OF EXAMPLE 218

[0187] 0.2 g of compound 11, 3,5-difluoro-4-hydroxyaniline and 0.75 mLof sulpholane were heated to 130° C. for 15 min, to 140° C. for 15 minand to 170° C. for 10 min. Then the mixture was combined with ether, thesupernatant solution was decanted off and the residue was crystallisedfrom methanol/ether and recrystallised again from methanol.

[0188] Yield: 0.15 g of white crystals. Melting point:>250° C.

SYNTHESIS OF EXAMPLE 4

[0189] 6.3 g of compound 11 were dissolved in 25 mL of sulpholane at100° C., then combined with 4.0 g of ethyl 4-aminobenzoate and heated to170° C. for 1 h. Then the mixture was combined with 50 mL of ether.After crystallisation started, a further 50 mL of ether and 50 mL ofmethanol were added. The crystals were recrystallised from methanol.

[0190] Yield: 6.6 g of a compound 12 (yellowish crystals), meltingpoint: from 65° C. decomposition sets in

[0191] 3.55 g of compound 12 were suspended in 250 mL of methanol and at60° C. combined with 25 mL of 4N sodium hydroxide solution. After 6 h,15 mL of glacial acetic acid were added, the resulting crystals werefiltered off and washed with methanol/ether.

[0192] Yield: 1.2 g of a compound 13 (white crystals)

[0193] 1.5 g of compound 13 were dissolved in 7.5 mL of thionyl chlorideand heated to 80° C. for 1 h. Then the thionyl chloride was eliminatedby distillation, the residue was stirred with ether, the crystals weresuction filtered and washed with ether.

[0194] Yield: 1.7 g of a compound 14 (yellow crystals)

[0195] 0.18 g of 3-aminopyridine were dissolved in 10 mL oftetrahydrofuran (THF) and combined with 0.4 mL of triethylamine. Then0.22 g of compound 14 were added and the mixture was stirred for 16 h atambient temperature. The mixture was evaporated to dryness, taken up inethyl acetate, extracted with water, evaporated down again and theproduct was crystallised from ethyl acetate.

[0196] Yield: 0.07 g (beige crystals), Melting point: 215-216° C.

SYNTHESIS OF EXAMPLE 58

[0197] 0.05 g of compound 13 were suspended in 10 mL of dichloromethane,then combined with 0.15 mL of DIPEA and 0.05 g of TBTU. The solution wasthen stirred for 30 min and combined with 0.01 mL of 4-picolylamine.After 18 h the mixture was combined with 20 mL of water, the organicphase was separated off and the product was purified by silica gelchromatography, then recrystallised from ethyl acetate/petroleum ether.

[0198] Yield: 0.044 g (white crystals), Melting point: 238-240° C.

EXAMPLES 65 AND 125

[0199] In order to synthesise the compounds 65 and 125, first anintermediate compound 18

[0200] is prepared as described hereinafter.

[0201] 28.3 g of isobutylamine, 36 g of ethyl R,S-2-bromopropionate and28 g of potassium carbonate were refluxed in 150 ml of ethyl acetate for6 h. After cooling the salt was suction filtered, the mother liquor wasconcentrated by evaporation.

[0202] The residue was combined with 100 ml of toluene and evaporated todryness.

[0203] Yield: 37.2 g of a compound 15 (yellow oil)

[0204] 38.4 g of 2,4-dichloro-5-nitropyrimidine were placed in 300 ml ofdiethylether, 30 g of potassium hydrogen carbonate in 300 ml of waterwere added and the mixture was cooled to 0° C. 37.0 g of compound 15were dissolved in 300 ml of diethylether and added dropwise at 0°-3° C.After 3 h the phases were separated, the organic phase was dried andevaporated to dryness.

[0205] Yield: 71.6 g of a compound 16

[0206] 40.0 g of compound 16 were dissolved in 300 ml of glacial aceticacid and heated to 70° C. After removal of the heat source, 30 g of ironwas added batchwise. The temperature rose to 110° C. The reactionmixture was cooled to 90° C. and stirred for 20 min. at thistemperature. Then it was filtered while hot and the filtrate wasconcentrated by evaporation. The residue was stirred with 300 ml ofwater and 300 ml of dichloromethane and filtered through kieselgur. Thephases were separated. The organic phase was washed with water, driedover MgSO₄ and evaporated to dryness. It was extracted from petroleumether.

[0207] Yield: 26.7 g of a compound 17

[0208] 15.0 g of compound 17 were placed in 100 ml of DMA, 4.13 ml ofmethyl iodide were added and the mixture was cooled to 5° C. 2.60 g ofNaH were added batchwise as a 60% dispersion in mineral oil. Thetemperature rose to 13° C. After 30 min. 300 ml of ice water were added,the crystals precipitated were suction filtered and washed withpetroleum ether.

[0209] Yield: 13.9 g of a compound 18 ¹H-NMR (250 MHz):=7.95 (1H, s),4.30 (m, 1H), 3.95 (m, 1H), 3.24 (s, 3H), 2.95 (m, 1H), 2.05 (m, 1H),1.30 (d, 3H), 0.96 (d, 3H), 0.92 (d, 3H).

SYNTHESIS OF EXAMPLE 65

[0210] 2.1 g of compound 18 were combined with ethyl 4-aminobenzoate in10 mL sulpholane and stirred for 2 h at 160° C. Then ether was added andthe crystals precipitated were washed with ether:

[0211] Yield: 3.0 g of a compound 19

[0212] 3 g of the compound 19 were combined with 200 mL of methanol and25 mL of 4N NaOH and stirred for 4 h at 60° C. Then glacial acetic acidwas added, the crystals precipitated were filtered off and washed withether.

[0213] Yield: 2.3 g of a compound 20 (white crystals)

[0214] 0.1 g of compound 20 were suspended in 3 mL of dichloromethaneand 3 mL of DMF, and then combined with 0.13 g of DIPEA, 0.095 g of TBTUand 0.045 g of hydroxybenzotriazole (HOBt). Then the solution wasstirred for 30 min and combined with 0.035 g of N-methyl-3-picolylamine.After 0.5 h the mixture was combined with water and 1 g of potassiumcarbonate, the aqueous phase was extracted twice with 50 mL of ethylacetate and the product was purified by silica gel chromatography andthen recrystallised from ethanol/acetone.

[0215] Yield: 0.08 g

SYNTHESIS OF EXAMPLE 125

[0216] 3.7 g of compound 20, 3.8 g of TBTU, 1.6 g of HOBt, 5 mL of DIPEAwere dissolved in 40 mL of DMF and stirred for 4 h at ambienttemperature. The mixture was evaporated down, taken up in 200 mL ofethyl acetate and extracted twice with 5 mL of 5% potassium carbonatesolution. The organic phase was evaporated down, the crystalsprecipitated were filtered off and washed with ethyl acetate and ether.

[0217] Yield: 1.65 g of a compound 21 (yellowish crystals)

[0218] 0.486 g of compound 21 were refluxed with 0.33 g of1,2-phenylenediamine in 10 mL of toluene for 0.5 h, then the mixture wasevaporated down. The residue was combined with 100 mL ethyl acetate, theorganic phase was extracted twice with water. The organic phase wasevaporated down, the crystals precipitated were suction filtered andwashed with a little ethyl acetate.

[0219] Yield: 0.25 g of a compound 22 (white crystals)

[0220] 0.22 g of compound 22 were stirred into 20 g of polyphosphoricacid for 0.5 h at 150° C., then the mixture was poured onto ice andammonia was added. It was then extracted twice with 100 mL of ethylacetate, the organic phase was washed with water and evaporated down.The precipitated product (crystals) was suction filtered and washed withethyl acetate and ether.

[0221] Yield: 0.115 g of yellowish crystals, Melting point: 287° C.(decomposition)

EXAMPLE 171

[0222] In order to synthesise compound 171 first an intermediatecompound 27 [sic]

[0223] 34.4 g of N-isopentyl-benzylamine, 36.2 g of ethyl2-bromo-propionate and 42.0 g of potassium carbonate were placed in 250ml of DMF and stirred for 3 h at 110° C. After cooling the inorganicsalts were filtered off, the filtrate was concentrated by evaporation.The residue was extracted with water and diethylether, the organic phasewas washed with water, dried and evaporated to dryness.

[0224] Yield: 55.5 g of a compound 23

[0225] 55.5 g of compound 23 were placed in 600 ml of ethanol, andhydrogenated with 20 ml of 32% HCl and 6 g of 10% Pd/C at 20° C. under 5bar for 20 min. Then it was filtered through kieselgur and concentratedby evaporation. The residue was combined with 400 ml of diethylether,the precipitate was suction filtered and washed with diethylether.

[0226] Yield: 23.5 g of a compound 24, melting point 105° C.

[0227] 23.5 g of compound 24 were dissolved in 200 ml of water andcombined with 20.0 g (0.103 mol) of 2,4-dichloro-5-nitropyrimidine in400 ml of diethylether. After the reaction mixture had been cooled to−10° C., 50.0 g (0.499 mol) of potassium carbonate were added batchwise.The mixture was stirred at −5° C. for 1 h and at 0° C. for 1 h, thenheated to ambient temperature. The aqueous phase was separated off, theorganic phase was washed with water, dried and evaporated to dryness.

[0228] Yield: 36.9 9 of a compound 25

[0229] 20.0 g of the compound 25 were dissolved in 280 ml of glacialacetic acid and heated to 70° C. After removal of the heat source 17 gof iron were added. The temperature rose to 100° C., then the mixturewas stirred for 30 min. at this temperature.

[0230] It was then filtered while hot and the filtrate was concentratedby evaporation. The residue was combined with 300 ml of dichloromethaneand 30 ml of 32% HCl, the phases were separated, the aqueous phase wasextracted with dichloromethane, the combined organic phases were washedwith water and aqueous ammonia solution, dried and evaporated todryness. The residue was extracted with diethylether.

[0231] Yield: 10.5 g of a compound 26, melting point: 182°-185° C.

[0232] 2.7 g of the compound 26 and 2.5 ml of methyl iodide were placedin 27 ml of DMA and cooled to −10° C. 0.45 g of NaH, 60% dispersion inmineral oil, was added and stirred for 30 min. at −5° C. Then 10 g ofice and 5 ml of 2N HCl were added and the mixture was concentrated byevaporation. The residue was extracted with ethyl acetate and water, theorganic phase was dried, evaporated to dryness and filtered throughsilica gel.

[0233] Yield: 3.0 g of compound 27 (oil) ¹H-NMR (250 MHz):=7.67 (1H, s),4.32-4.07 (m, 2H), 3.32 (s, 3H), 3.08 (m, 1H), 1.70-1.50 (m, 3H), 1.42(d, 3H), 0.95 (m, 6H).

SYNTHESIS OF EXAMPLE 171

[0234] 0.28 g of compound 27, 0.9 mL of sulpholane and 0.22 g ofp-aminobenzoic acid-benzylamide were stirred for 0.5 h at 170° C., thenthe mixture was combined with ether and the crystals were filtered off.The product was recrystallised from ethanol.

[0235] Yield: 0,15 g, melting point: 228-240° C. (yellowish crystals)

[0236] The compounds of formula (I) listed in Table 1 are obtainedanalogously to the process described above.

[0237] The abbreviations X₂, X₃, X₄, X₅ and X₆ used in Table 1 in eachcase denote a link to a position in the general formula shown underTable 1 instead of the corresponding groups R², R³, R⁴, R⁵ and R⁶. TABLE1

config. mp. Ex. R² R³ R⁴ R³ or R⁴ R⁵ R⁶ [° C.] 1

H H rac.

2

H rac.

208 3

H rac.

241 4

H rac.

5

H rac.

175 6

H R

190 7

H rac.

8

H rac.

200 9

H rac.

168 10

H rac.

190 11

H rac.

12

H rac.

13

H rac.

145 14

H rac.

15

H rac.

55 16

H rac.

250 17

H rac.

204 18

H rac.

19

H rac.

20

H R

221 21

H rac.

172 22

H rac.

221 23

H rac.

24

H rac.

210 25

H R

213 26

H rac.

188 27

H rac.

28

H S

29

H rac.

178 30

H R

175 31

H rac.

32

H rac.

221 33

H R

124 34

H rac.

136 35

H rac.

162 36

H rac.

169 37

H rac.

219 38

H rac.

179 39

H rac.

211 40

H rac.

41

H rac.

42

H R

100 43

H rac.

175 44

H rac.

203 45

H rac.

165 46

H rac.

47

H rac.

48

H rac.

49

H rac.

50

H rac.

212 51

H S

52

H rac.

53

H rac.

54

H rac.

55

H rac.

191 56

H rac.

158 57

H rac.

230 58

H rac.

59

H R

125 60

H H rac.

250 61

H rac.

62

H rac.

169 63

H rac.

178 64

H rac.

65

H rac.

66

H R

225 67

H rac.

68

H rac.

69

H rac.

70

H rac.

71

H rac.

72

H rac.

73

H rac.

74

167 75

H rac.

76

H rac.

246 77

H rac.

78

H rac.

172 79

H rac.

170 80

rac.

222 81

H rac.

187 82

H rac.

215 83

199 84

rac.

127 85

H rac.

86

H rac.

169 87

H rac.

250 88

H rac.

233 89

H rac.

160 90

H rac.

154 91

H rac.

92

H rac.

93

H rac.

94

H R

95

H rac.

150 96

rac.

300 97

H rac.

243 98

H rac.

209 99

H rac.

182 100

H rac.

101

H R

232 102

H rac.

103

H rac.

104

H rac.

146 105

H rac.

209 106

H rac.

286 107

H rac.

108

H R

202 109

H rac.

180 110

H rac.

111

H rac.

250 112

H rac.

113

H rac.

114

X₃—CH₃

237 115

H rac.

135 116

H rac.

117

H rac.

118

H rac.

119

H rac.

213 120

H rac.

198 121

H rac.

122

H rac.

123

H rac.

124

H rac.

125

H rac.

287 126

H rac.

127

H rac.

128

H rac.

129

H rac.

247 130

H rac.

131

X₃—CH₃

281 132

H rac.

133

H rac.

134

H rac.

208 135

H rac.

136

H R

192 137

H rac.

212 138

H rac.

139

H rac.

140

H rac.

148 141

H rac.

142

H rac.

143

H rac.

186 144

199 145

H rac.

214 146

H rac.

155 147

H rac.

148

H rac.

149

H rac.

245 150

H rac.

151

H rac.

152

H rac.

153

H rac.

154

H rac.

155

H rac.

156

H rac.

265 157

H rac.

192 158

H rac.

222 159

H rac.

221 160

298 161

H rac.

181 162

H S

163

172 164

H rac.

227 165

H rac.

258 166

X₃—CH₃

266 167

H rac.

168

rac.

159 169

250 170

H rac.

213 171

H rac.

228 172

H rac.

181 173

H rac.

182 174

H rac.

175

H rac.

197 176

H rac.

177

H rac.

216 178

H rac.

200 179

H rac.

197 180

rac.

143 181

234 182

H rac.

183

H rac.

169 184

H rac.

185

H rac.

198 186

202 187

H rac.

200 188

H rac.

189

H rac.

198 190

196 191

X₃—CH₃

253 192

H rac.

193

H rac.

201 194

H rac.

250 195

H rac.

198 196

H rac.

245 197

H rac.

198

H rac.

199

H rac.

200

X₃—CH₃

198 201

H H rac.

202

H rac.

203

H rac.

198 204

H rac.

205

H rac.

206

H rac.

207

H rac.

184 208

H rac.

253 209

H rac.

240 210

H rac.

211

X₃—CH₃

266 212

H rac.

213

H rac.

214

H rac.

215

H rac.

232 216

H rac.

217

H rac.

218

H rac.

>250 219

H rac.

260 (Zers.) 220

H R

190 221

H R

228 222

H R

223

H R

243 224

H R

258 225

H R

226

H R

227

H R

241 228

H R

229

H R

300 230

H R

200 231

H R

232 232

H R

149 234

H R

197 235

H R

226 236

H R

182 237

H R

238

H R

239

H R

240

H R

241

H R

194 242

H R

200 243

H R

156 244

H R

195 245

H R

147 246

H R

247

H R

85 248

H R

249

H R

250

H R

158 251

H R

188 252

H R

245 253

H R

254

H R

128 255

H R

256

H R

181 257

H R

217 258

H R

259

H R

260

H R

261

H R

230 262

H R

193 263

H R

264

H R

152 265

H R

207 266

H R

229 267

H R

268

H R

183 269

H R

270

H R

161 271

H R

282 272

H R

157 273

H R

129 274

H R

164 275

H R

219 276

H R

277

H R

200 278

H R

200 279

H R

280

H R

281

H R

282

H R

283

H R

277 284

H R

197 285

H R

286

H R

182 287

H R

288

H R

163 289

H R

212 290

H R

291

H R

292

H R

293

H R

200 294

H R

144 295

H R

221 296

H R

150 297

H R

298

H R

163 299

H R

300

H R

98 301

H R

302

H R

303

H R

304

H R

305

H R

306

H R

307

H R

179 308

H R

174 309

H R

231 310

H R

311

H R

312

H R

313

H R

314

H R

69 315

H R

200 316

H R

210 317

H R

131 318

H R

319

H R

145 320

H R

321

H R

322

H R

149 323

H R

324

H R

325

H R

326

H R

327

H R

328

H R

176 329

H R

330

H R

331

H R

332

H R

333

H R

334

X₃—CH₃

250 335

X₃—CH₃

236

[0238] As has been found, the compounds of general formula (I) arecharacterised by their wide range of applications in the therapeuticfield. Particular mention should be made of those applications in whichthe inhibition of specific cell cycle kinases, particularly theinhibiting effect on the proliferation of cultivated human tumour cellsbut also the proliferation of other cells, such as endothelial cells,for example, plays a part.

[0239] As could be demonstrated by FACS analysis, the inhibition ofproliferation brought about by the compounds according to the inventionis mediated by the arrest of the cells, particularly at the G2/M phaseof the cell cycle. The cells arrest, independently of the cells used,for a specific length of time in this phase of the cell cycle beforeprogrammed cell death is initiated. An arrest in the G2/M phase of thecell cycle is triggered, for example, by the inhibition of specific cellcycle kinases. Studies in model organisms such as Schizosaccharomycespombe or Xenopus, or investigations in human cells have shown that thetransition from the G2 phase to mitosis is regulated by the CDK1/cyclinB kinase (Nurse, 1990). This kinase, which is also known as the “mitosispromoting factor” (MPF), phosphorylates and thereby regulates a numberof proteins, such as e.g. nuclear lamins, kinesin-like motor proteins,condensins and Golgi matrix proteins, which play an important part inthe breakdown of the nuclear envelope, in centrosome separation, theformation of the mitotic spindle apparatus, chromosome condensation andthe breakdown of the Golgi apparatus (Nigg. E., 2001). A murine cellline with a temperature-sensitive CDK1 kinase mutant shows a rapidbreakdown of the CDK1 kinase and a subsequent arrest in the G2/M phaseafter a temperature increase (Th'ng et al., 1990). The treatment ofhuman tumour cells with inhibitors against CDK1/cyclin B such as e.g.butyrolactone also leads to an arrest in the G2/M phase and subsequentapoptosis (Nishio, et al. 1996). Another kinase which is involved in theG2 and mitosis phase is polo-like kinase 1 (Plk1), which is responsiblefor the maturation of the centrosomes, for the activation of thephosphatase Cdc25C, as well as for the activation of the anaphasepromoting complex (Glover et al., 1998, Qian, et al., 2001). Theinjection of Plk1 antibodies leads to a G2 arrest in untransformed cellswhereas tumour cells arrest in the mitosis phase (Lane and Nigg, 1996).In addition, the protein kinase aurora B has been described as having anessential function during entry into mitosis. Aurora B phosphorylateshistone H3 at Ser11 and thereby initiates chromosome condensation (Hsu,J. Y. et al., 2000). A specific cell cycle arrest in the G2/M phase may,however, also be triggered e.g. by the inhibition of specificphosphatases such as e.g. Cdc25C (Russell and Nurse, 1986). Yeasts witha defective cdc25 gene arrest in the G2 phase, while overexpression ofcdc25 leads to early entry into the mitosis phase (Russell and Nurse,1987). However, an arrest in the G2/M phase can also be triggered by theinhibition of certain motor proteins, so-capped kinesins such as e.g.Eg5 (Mayer et al., 1999), or by agents which stabilise or destabilisemicrotubules (e.g. colchicin, taxol, etoposide, vinblastin, vincristin)(Schiff and Horwitz, 1980).

[0240] In view of their biological properties the compounds of generalformula I according to the invention, their isomers and theirphysiologically acceptable salts are suitable for the treatment ofdiseases characterised by excessive or abnormal cell proliferation.

[0241] Such diseases include, for example: viral infections (e.g. HIVand Kaposi's sarcoma); inflammatory and autoimmune diseases (e.g.colitis, arthritis, Alzheimer's disease, glomerulonephritis and woundhealing); bacterial, fungal and/or parasitic infections; leukaemias,lymphoma and solid tumours; skin diseases (e.g. psoriasis); bonediseases; cardiovascular diseases (e.g. restenosis and hypertrophy).They are also suitable for protecting proliferating cells (e.g. hair,intestinal, blood and progenitor cells) from damage to their DNA causedby radiation, UV treatment and/or cytostatic treatment (Davis et al.,2001).

[0242] The new compounds may be used for the prevention, short-term orlong-term treatment of the abovementioned diseases, also in combinationwith other active substances used for the same indications, e.g.cytostatics.

[0243] The activity of the compounds according to the invention wasdetermined in the cytotoxicity test on cultivated human tumour cellsand/or in a FACS analysis, for example on HeLaS3 cells. In both testmethods, the compounds exhibited a good to very good activity, i.e. forexample an EC₅₀ value in the HeLaS3 cytotoxicity test of less than 5μmol, generally less than 1 μmol.

[0244] Measurement of Cytotoxicity on Cultivated Human Tumour Cells

[0245] To measure the cytotoxicity on cultivated human tumour cells,cells of the cervical cancer tumour cell line HeLaS3 (obtained fromAmerican Type Culture Collection (ATCC)) in Ham's F12 Medium (LifeTechnologies) and 10% foetal calf serum (Life Technologies) werecultivated and harvested in the logarithmic growth phase. Then theHeLaS3 cells were placed in 96-well plates (Costar) at a density of 1000cells per well and incubated overnight in an incubator (at 37° C. and 5%CO₂), while on each plate 6 wells were filled only with medium (3 wellsas a control of the medium, 3 wells for incubation with reducedAlamarBlue). The active substances were added to the cells in variousconcentrations (dissolved in DMSO; final concentration: 1%) (in eachcase as a triple measurement). After 72 hours' incubation, 20 μl ofAlamarBlue (AccuMed International) were added to each well, and thecells were incubated for a further 7 hours. As a control, 20 μl ofreduced Alamar Blue (AlamarBlue reagent which had been autoclaved for 30min) were added to 3 wells. After 7 h incubation the colour change ofthe AlamarBlue reagent in the individual wells was determined in aPerkin Elmer fluorescence spectrophotometer (excitation 530 nm, emission590 nm, slits 15, integrate time 0.1). The amount of AlamarBlue reagentreacted represents the metabolic activity of the cells. The relativecell activity was calculated as a percentage of the control (HeLa S3cells without inhibitor) and the active substance concentration whichinhibits the cell activity by 50% (IC⁵⁰) was obtained. The values werecalculated from the average of three individual measurements, correctingfor the control value (medium control).

[0246] FACS Analysis

[0247] Propidium iodide (PI) binds stoichiometrically to double-strandedDNA, and is thus suitable for determining the percentage of cells in theG1, S and G2/M phase of the cell cycle on the basis of the cell DNAcontent. Cells in the G0 and G1 phase have a diploid DNA content (2N),whereas cells in G2 or mitosis have a 4N DNA content. For PI staining,0.4 million HeLaS3 cells were seeded, for example, on a 75 cm² cellculture flask, and after 24 h either 1% DMSO was added as control or thesubstance was added in various concentrations (in 1% DMSO). The cellswere incubated for 24 h with the substance or with DMSO, before thecells were washed with 2×PBS and detached with trypsin/EDTA. The cellswere centrifuged (1000 rpm, 5 min, 4° C.), and the cell pellet waswashed 2× with PBS, before the cells were resuspended in 0.1 ml of PBS.Then the cells were fixed with 80% ethanol for 16 hours at 4° C. oralternatively for 2 hours at −20° C. The fixed cells (10⁶ cells) werecentrifuged (1000 rpm, 5 min, 4° C.), washed with PBS and thencentrifuged again. The cell pellet was resuspended in 2 ml of TritonX-100 in 0.25% PBS, and incubated for 5 min on ice, before 5 ml of PBSwere added and the mixture was centrifuged again. The cell pellet wasresuspended in 350 μl of PI stain solution (0.1 mg/ml of Raze A, 10μg/ml of presidium iodide in 1×PBS). The cells were incubated for 20 minin the dark with the stain buffer before being transferred into samplemeasuring vessels for the FACS scan. The DNA measurement was carried outin a Becton Dickinson FACS Analyzer, with an argon laser (500 mW,emission 488 nm), and the DNA Cell Quest Program (BD). The logarithmicPI fluorescence was determined with a band-pass filter (BP 585/42). Thecell populations in the individual phases of the cell cycle werequantified with the ModFit LT program of Becton Dickinson.

[0248] The compounds of general formula (I) may be used on their own orcombined with other active substances according to the invention,optionally also in conjunction with other pharmacologically activesubstances. Suitable preparations include for example tablets, capsules,suppositories, solutions, particularly solutions for injection (s.c.,i.v., i.m.) and infusion, syrups, emulsions or dispersible powders. Theamount of pharmaceutically active compound in each case should be in therange from 0.1-90 wt. %, preferably 0.5-50 wt. % of the totalcomposition, i.e. in amounts which are sufficient to achieve the dosagerange given below. The doses specified may, if necessary, be givenseveral times a day.

[0249] Suitable tablets may be obtained, for example, by mixing theactive substance(s) with known excipients, for example inert diluentssuch as calcium carbonate, calcium phosphate or lactose, disintegrantssuch as corn starch or alginic acid, binders such as starch or gelatine,lubricants such as magnesium stearate or talc and/or agents for delayingrelease, such as carboxymethyl cellulose, cellulose acetate phthalate,or polyvinyl acetate. The tablets may also comprise several layers.

[0250] Coated tablets may be prepared accordingly by coating coresproduced analogously to the tablets with substances normally used fortablet coatings, for example collidone or shellac, gum arabic, talc,titanium dioxide or sugar. To achieve delayed release or preventincompatibilities the core may also consist of a number of layers.Similarly the tablet coating may consist of a number of layers toachieve delayed release, possibly using the excipients mentioned abovefor the tablets.

[0251] Syrups or elixirs containing the active substances orcombinations thereof according to the invention may additionally containa sweetener such as saccharin, cyclamate, glycerol or sugar and aflavour enhancer, e.g. a flavouring such as vanillin or orange extract.They may also contain suspension adjuvants or thickeners such as sodiumcarboxymethyl cellulose, wetting agents such as, for example,condensation products of fatty alcohols with ethylene oxide, orpreservatives such as p-hydroxybenzoates.

[0252] Solutions for injection and infusion are prepared in the usualway, e.g. with the addition of preservatives such as p-hydroxybenzoates,or stabilisers such as alkali metal salts of ethylenediamine tetraaceticacid, optionally using emulsifiers and/or dispersants, while if water isused as the diluent organic solvents may optionally be used assolubilisers or auxiliary solvents, and transferred into injection vialsor ampoules or infusion bottles.

[0253] Capsules containing one or more active substances or combinationsof active substances may for example be prepared by mixing the activesubstances with inert carriers such as lactose or sorbitol and packingthem into gelatine capsules.

[0254] Suitable suppositories may be made for example by mixing withcarriers provided for this purpose, such as neutral fats orpolyethyleneglycol or the derivatives thereof.

[0255] Suitable excipients may be, for example, water, pharmaceuticallyacceptable organic solvents, such as paraffins (e.g. petroleumfractions), oils of vegetable origin (e.g. groundnut or sesame oil),mono- or polyfunctional alcohols (e.g. ethanol or glycerol), carrierssuch as e.g. natural mineral powders (e.g. kaolin, clays, talc, chalk),synthetic mineral powders (e.g. highly dispersed silica and silicates),sugar (e.g. glucose, lactose and dextrose), emulsifiers (e.g. lignin,spent sulphite liquors, methylcellulose, starch andpolyvinylpyrrolidone) and lubricants (e.g. magnesium stearate, talc,stearic acid and sodium lauryl sulphate).

[0256] The preparations are administered in the usual way, preferably byoral or transdermal route, particularly preferably by oral route. Whenadministered orally the tablets may, of course, contain additives, suchas e.g. sodium citrate, calcium carbonate and dicalcium phosphatetogether with various additives, such as starch, preferably potatostarch, gelatine and the like, in addition to the abovementionedcarriers. Lubricants such as magnesium stearate, sodium laurylsulphateand talc may also be used to form tablets. In the case of aqueoussuspensions the active substances may be combined with various flavourenhancers or colourings in addition to the abovementioned excipients.

[0257] For parenteral use, solutions of the active substances may beprepared using suitable liquid carrier materials.

[0258] The dosage for intravenous use is 1-1000 mg per hour, preferablybetween 5-500 mg per hour.

[0259] However, it may optionally be necessary to deviate from theamounts specified, depending on the body weight or method ofadministration, the individual response to the medication, the nature ofthe formulation used and the time or interval over which it isadministered. Thus, in some cases, it may be sufficient to use less thanthe minimum quantity specified above, while in other cases the upperlimit specified will have to be exceeded. When large amounts areadministered it may be advisable to spread them over the day in a numberof single doses.

[0260] The formulation examples that follow illustrate the presentinvention without restricting its scope:

Examples of Pharmaceutical Formulations

[0261] A) Tablets per tablet active substance 100 mg lactose 140 mg cornstarch 240 mg polyvinylpyrrolidone  15 mg magnesium stearate  5 mg 500mg

[0262] The finely ground active substance, lactose and some of the cornstarch are mixed together. The mixture is screened, then moistened witha solution of polyvinylpyrrolidone in water, kneaded, wet-granulated anddried. The granules, the remaining corn starch and the magnesiumstearate are screened and mixed together. The mixture is compressed toproduce tablets of suitable shape and size. B) Tablets per tablet activesubstance  80 mg lactose  55 mg corn starch 190 mg microcrystallinecellulose  35 mg polyvinylpyrrolidone  15 mg sodium-carboxymethyl starch 23 mg magnesium stearate  2 mg 400 mg

[0263] The finely ground active substance, some of the corn starch,lactose, microcrystalline cellulose and polyvinylpyrrolidone are mixedtogether, the mixture is screened and worked with the remaining cornstarch and water to form a granulate which is dried and screened. Thesodiumcarboxymethyl starch and the magnesium stearate are added andmixed in and the mixture is compressed to form tablets of a suitablesize. C) Ampoule solution active substance 50 mg sodium chloride 50 mgwater for inj.  5 ml

[0264] The active substance is dissolved in water at its own pH oroptionally at pH 5.5 to 6.5 and sodium chloride is added to make itisotonic. The solution obtained is filtered free from pyrogens and thefiltrate is transferred under aseptic conditions into ampoules which arethen sterilised and sealed by fusion. The ampoules contain 5 mg, 25 mgand 50 mg of active substance.

1. A method of treating a disease or condition chosen from cancer,infections, inflammatory and autoimmune diseases said method comprisingadministering to a patient in need thereof a therapeutically effectiveamount of a compound of the formula (I),

wherein R¹ denotes a group selected from among hydrogen, NH₂, XH,halogen and a C₁-C₃-alkyl group optionally substituted by one or morehalogen atoms, R² denotes a group selected from among hydrogen, CHO, XH,—X—C₁-C₂-alkyl and an optionally substituted C₁-C₃-alkyl group, R³, R⁴are identical or different and denote a group selected from amongoptionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl,aryl, heteroaryl, C₃-C₈-cycloalkyl, C₃-C₈-heterocycloalkyl, —X-aryl,—X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR⁸-aryl,—NR⁸-heteroaryl, —NR⁸-cycloalkyl,- and —NR⁸-heterocycloalkyl, or a groupselected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂, COR⁸ and XR⁸, orR³ and R⁴ together denote a 2- to 5-membered alkyl bridge which maycontain 1 to 2 heteroatoms, R⁵ denotes hydrogen or a group selected fromamong optionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,C₂-C₁₀-alkynyl, aryl, heteroaryl and —C₃-C₆-cycloalkyl , or R³ and R⁵ orR⁴ and R⁵ together denote a saturated or unsaturated C₃-C₄-alkyl bridgewhich may contain 1 to 2 heteroatoms, R⁶ denotes optionally substitutedaryl or heteroaryl, R⁷ denotes hydrogen or —CO—X—C₁-C₄-alkyl, and X ineach case independently of one another denotes O or S, and R⁸ in eachcase independently of one another denotes hydrogen or a group selectedfrom among optionally substituted C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl and phenyl, or the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.
 2. Amethod of treating a disease or condition chosen from HIV, Kaposi'ssarcoma, colitis, arthritis, Alzheimer's disease, glomerulonephritis,conditions related to wound healing, bacterial, fungal and/or parasiticinfections, leukaemias, lymphoma, solid tumours, psoriasis, bonediseases and cardiovascular disease comprising administering to apatient in need thereof a therapeutically effective amount of a compoundof formula (I)

wherein R¹ denotes a group selected from among hydrogen, NH₂, XH,halogen and a C₁-C₃-alkyl group optionally substituted by one or morehalogen atoms, R² denotes a group selected from among hydrogen, CHO, XH,—X—C₁-C₂-alkyl and an optionally substituted C₁-C₃-alkyl group, R³, R⁴are identical or different and denote a group selected from amongoptionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl,aryl, heteroaryl, C₃-C₈-cycloalkyl, C₃-C₈-heterocycloalkyl, —X-aryl,—X-heteroaryl, —X-cycloalkyl, —X-heterocycloalkyl, —NR⁸-aryl,—NR⁸-heteroaryl, —NR⁸-cycloalkyl,- and —NR⁸-heterocycloalkyl, or a groupselected from among hydrogen, halogen, COXR⁸, CON(R⁸)₂, COR⁸ and XR⁸, orR³ and R⁴ together denote a 2- to 5-membered alkyl bridge which maycontain 1 to 2 heteroatoms, R⁵ denotes hydrogen or a group selected fromamong optionally substituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl,C₂-C₁₀-alkynyl, aryl, heteroaryl and —C₃-C₆-cycloalkyl , or R³ and R⁵ orR⁴ and R⁵ together denote a saturated or unsaturated C₃-C₄-alkyl bridgewhich may contain 1 to 2 heteroatoms, R⁶ denotes optionally substitutedaryl or heteroaryl, R⁷ denotes hydrogen or —CO—X—C₁-C₄-alkyl, and X ineach case independently of one another denotes O or S, and R⁸ in eachcase independently of one another denotes hydrogen or a group selectedfrom among optionally substituted C₁-C₄-alkyl, C₂-C₄-alkenyl,C₂-C₄-alkynyl and phenyl, or the tautomers, the racemates, theenantiomers, the diastereomers and the mixtures thereof, and optionallythe pharmacologically acceptable acid addition salts thereof.
 3. Themethods according to claims 1 or 2 wherein for the formula (I) R¹denotes hydrogen, R² denotes a group selected from among a CHO, OH, andCH₃ group, R³, R⁴ are identical or different and denote a group selectedfrom among hydrogen, optionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl,C₂-C₆-alkynyl, C₃-C₇-cycloalkyl, or R³ and R⁴ together denote aC₂-C₅-alkyl bridge, R⁵ denotes a group selected from among optionallysubstituted C₁-C₁₀-alkyl, C₂-C₁₀-alkenyl, C₂-C₁₀-alkynyl,C₃-C₆-cycloalkyl and C₃-C₆-cycloalkenyl, or R³ and R⁵ or R⁴ and R⁵together denote a saturated or unsaturated C₃-C₄-alkyl bridge which maycontain 1 to 2 heteroatoms, and R⁷ denotes hydrogen.
 4. The methodsaccording to claim 3, wherein for the formula (I) R⁶ denotes a group ofgeneral formula

wherein n denotes 1, 2, 3 or 4, R⁹ denotes a group selected from amongoptionally substituted C₁-C₆-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl,—CONH—C₁-C₁₀-alkylene, —O-aryl, —O-heteroaryl, —O-cycloalkyl,—O-heterocycloalkyl, aryl, heteroaryl, cycloalkyl and heterocycloalkylor a group selected from among —O—C₁-C₆-alkyl-Q¹,—CONR⁸—C₁-C₁₀-alkyl-Q¹, —CONR⁸—C₂-C₁₀-alkenyl-Q¹, —CONR⁸—Q², halogen,OH, —SO₂R⁸, —SO₂N(R⁸)₂, —COR⁸, —COOR⁸, —N(R⁸)₂, —NHCOR⁸, CONR⁸OC₁-C₁₀alkylQ¹ and CONR⁸OQ², Q¹ denotes hydrogen, —NHCOR⁸, or a group selectedfrom among an optionally substituted —NH-aryl, —NH-heteroaryl, aryl,heteroaryl, C₃-C₈-cycloalkyl- and heterocycloalkyl group, Q² denoteshydrogen or a group selected from among an optionally substituted aryl,heteroaryl, C₃-C₈-heterocycloalkyl, C₃-C₈-cycloalkyl- andC₁-C₄-alkyl-C₃-C₈-cycloalkyl group, R¹⁰ is identical or different anddenotes a group selected from among optionally substituted C₁-C₆-alkyl ,C₂-C₆-alkenyl and C₂-C₆-alkynyl, —O—C₁-C₆-alkyl, —O—C₂-C₆-alkenyl,—O—C₂-C₆-alkynyl, C₃-C₆-heterocycloalkyl and C₃-C₆-cycloalkyl, or agroup selected from among hydrogen, —CONH₂, —COOR⁸, —OCON(R⁸)₂, —N(R⁸)₂,—NHCOR⁸, —NHCON(R⁸)₂, —NO₂ and halogen, or adjacent groups R⁹ and R¹⁰together denote a bridge of the formula

Y denotes O, S or NR¹¹, m denotes 0, 1 or 2 R¹¹ denotes hydrogen orC₁-C₂-alkyl, and R¹² denotes hydrogen or a group selected from amongoptionally substituted phenyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, —C₁-C₃-alkyl-phenyl, —C₁-C₃-alkyl-pyridyl,—C₁-C₃-alkyl-pyrazinyl, —C₁-C₃-alkyl-pyrimidinyl and—C₁-C₃-alkyl-pyridazinyl, and R¹³ denotes C₁-C₆-alkyl.
 5. The methodsaccording to claim 4, wherein for the formula (I) R¹ denotes hydrogen,R² denotes CH₃, and R⁷ denotes hydrogen.
 6. A method of treating adisease or condition chosen from cancer, infections, inflammatory andautoimmune diseases said method comprising administering to a patient inneed thereof a therapeutically effective amount of a compound of theformula (II),

wherein R¹-R⁵ and X have the meanings given in claim
 1. 7. A method oftreating a disease or condition chosen from HIV, Kaposi's sarcoma,colitis, arthritis, Alzheimer's disease, glomerulonephritis, conditionsrelated to wound healing, bacterial, fungal and/or parasitic infections,leukaemias, lymphoma, solid tumours, psoriasis, bone diseases andcardiovascular disease comprising administering to a patient in needthereof a therapeutically effective amount of a compound of the formula(II),

wherein R¹-R⁵ and X have the meanings given in claim 1.